Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients

Open Label Randomized Bioequivalence Study to Evaluate the Pharmacokinetic and Safety Profile of Bevacizumab Biosimilar (BEVZ92) vs Bevacizumab (AVASTIN®), Both With FOLFOX or FOLFIRI, in First-line Treatment for mCRC Patients

This is a multicenter, open label, randomized bioequivalence study of BEVZ92 (bevacizumab biosimilar) and Avastin® with 2 parallel arms to compare the pharmacokinetic (PK) profile of BEVZ92 and Avastin® in combination with FOLFOX (any) or FOLFIRI chemotherapy.

FOLFOX (any) or FOLFIRI will be chosen as per investigator criteria based on the hospital standard of care.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer (mCRC)
• Intervention / Treatment: Drug: Bevacizumab biosimilar (BEVZ92); Drug: Avastin® (bevacizumab, reference product)

Detailed Description

Planned enrolment duration: 12 months. Pre-treatment period (included in enrolment period): 1 month. Treatment period: Patients will continue treatment until disease progression or unacceptable toxicity, or withdrawal of consent.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo"
  • Rosario, Argentina
    • Instituto Oncológico de Rosario
• Brazil
  • Barretos, Brazil
    • Fundacao Pio XII - Hospital do Cancer de Barretos
  • Ijui, Brazil
    • Hospital Caridade
  • Porto Alegre, Brazil
    • Hospital Sao Lucas da PUCRS
  • São Paulo, Brazil
    • Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC
  • São Paulo, Brazil
    • Hosp. A.C Camargo
  • São Paulo, Brazil
    • Instituto do Cancer del estado de S. Paulo (ICEPS )
• India
  • Chennai, India
    • Sri Ramachandra Hospital
  • Mumbai, India
    • Tata Hospital
  • Nagpur, India
    • Central India Canter Research Institute
  • Nashik, India
    • Curie Manavta Cancer Center
  • Thiruvananthapuram, India
    • Regional Cancer Center & Medical College
  • Gujarat
    • Karamsad, Gujarat, India, 388 325
      • M S Patel Cancer Centre- Shree Krishna Hospital
• Spain
  • Madrid, Spain
    • Centro Oncologico Clara Campal
• Ukraine
  • Dnipropetrovsk, Ukraine
    • Dnipropetrovsk City Multiple-discipline Clinical Hospital №4
  • Kharkiv, Ukraine
    • Kharkiv Regional Clinical Oncology Center
  • Lviv, Ukraine
    • Danylo Halytskiy Lviv National Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy.
2. Patient with mCRC for whom bio-chemotherapy is indicated.
3. Patients must have at least one measurable non-irradiated site of disease according to RECIST (version 1.1) criteria. If the patient has had previous irradiation of the marker lesion(s), there must be evidence of progression since the radiation.
4. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
6. Adequate bone marrow function
7. Adequate liver function defined within specific parameters
8. Adequate renal function defined within specific parameters
9. Adequate coagulation parameters defined within specific parameters
10. Negative pregnancy test for females of a childbearing potential.
11. Use of an effective form of contraception during the study (for subjects of childbearing potential and their partners).
12. Life expectation ≥ 3 months

Exclusion Criteria:

1. Prior treatment for advanced or metastatic colorectal cancer.
2. Prior treatment with an anti-angiogenesis agent, in either the neoadjuvant or adjuvant setting.
3. Concurrent use of investigational anti-neoplastic agents (including up to 4 weeks prior to enrolment).
4. History of any other malignancy unless the malignancy is in complete remission and the patient has been off all therapy for that malignancy for at least 5 years.
5. Chronic treatment with systemic steroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed.
6. Scheduled immunization with attenuated live vaccines during study period or within 1 week prior to study entry.
7. Uncontrolled brain or lepto-meningeal metastases, including patients who continue to require glucocorticoids for brain or lepto-meningeal metastases.
8. Patients with active bleeding or history of bleeding diathesis on oral anti-vitamin K medication (except low dose coumadin) within the past 6 month prior to randomization or coagulopathy.
9. Patients with history of cerebral vascular accident, transient ischemic attack, or subarachnoid haemorrhage within the past 6 month prior to randomization.
10. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
11. Patients with serious non-healing wound, ulcer, bone fracture, or with a major surgical procedure, or significant traumatic injury within 4 weeks prior to randomization
12. Patients with clinical symptoms or signs of gastrointestinal obstruction that require parenteral hydration and/or nutrition.
13. Patients with history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months prior to randomization.
14. Patients with history of hypersensitivity to any of the study drugs or ingredients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bevacizumab biosimilar (BEVZ92); Bevacizumab 25 mg/mL (strength: 100 mg/4 mL).	Drug: Bevacizumab biosimilar (BEVZ92); Active ingredient Bevacizumab 25 mg/mL (strength = 100 mg/4 mL). 30-minute* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri). FOLFIRI = Folinic Acid + Fluorouracil + Irinotecan FOLFOX = Folinic Acid + Fluorouracil + Oxaliplatin Treatment will continue until disease progression, unacceptable toxicity, patient withdraws consent or death (whichever occurs first). *The first infusion will be given over 90 minutes. If it is well tolerated, the second infusion can be given over 60 minutes. If it is well tolerated, subsequent infusions can be given over 30 minutes. The FOLFOX (any) or FOLFIRI regimen will be chosen as per investigator's criteria based on the hospital standard of care.; Other Names: FOLFOX = Folinic acid + Fluorouracil + Oxaliplatin; FOLFIRI = Folinic acid + Fluorouracil + Irinotecan
Active Comparator: Avastin® (bevacizumab, ref. product); Bevacizumab 25mg/ml (strength: 100mg/4ml)	Drug: Avastin® (bevacizumab, reference product); Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy. Treatment will continue until disease progression, unacceptable toxicity, patient withdraws consent or death (whichever occurs first). *The first infusion will be given over 90 minutes. If the first infusion is well tolerated, the second infusion can be given over 60 minutes. If this infusion is well tolerated, subsequent infusions can be given over 30 minutes. The FOLFOX (any) or FOLFIRI regimen will be chosen as per investigator's criteria based on the hospital standard of care.; Other Names: FOLFOX = Folinic acid + Fluorouracil + Oxaliplatin; FOLFIRI = Folinic acid + Fluorouracil + Irinotecan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin®	To compare the pharmacokinetic (PK) profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated AUC calculated from start of the first infusion until start of the second infusion (i.e. at Cycle 1; AUC0-336h) For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%.	AUC0-336 hrs: 0 to 336 hours after start of the first infusion
AUC at Steady State (AUCss) of BEVZ92 and Avastin®	To compare the PK profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated area under the concentration-versus-time curve calculated over a dosage interval at steady state (i.e. at Cycle 7; AUCss). For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%.	AUCss: 0 to 336 hours after the administration of Cycle 7 infusion (Week 13).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin®	Compare the safety profile by means of the frequency and severity of TEAEs and SAEs reported in each treatment arm.	From first study dose and up to 30 days after the end of study treatment for each patient, for an average of 11 months
Anti-Drug Antibody (ADA) of BEVZ92 and Avastin®	Immunogenicity profile by means of measurement of ADA developed de novo (seroconversion) after cycle 5, cycle 8, and 12 months after first drug administration (pre-dose).	At baseline, and on Day 1 (pre-dose) of Cycles: 1, 5 and 8, and 12 months after first drug administration
Objective Response Rate (ORR) of BEVZ92 and Avastin®	To compare efficacy in terms of ORR between arms. Clinical and radiological tumor assessments were performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans. Objective response (OR) is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR by the end of the study were considered non-responders.	Every four weeks. Up to 48 weeks
Cmax,sd of BEVZ92 and Avastin®	Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd )	Cmax, sd: 0 to 336 hours after start of the first infusion.
Progression-free Survival (PFS) of BEVZ92 and Avastin®	Compare PFS between the randomized treatment arms. Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions plus 5 mm absolute increase, and/or unequivocal progression of known non-target lesion, and/or the appearance of new lesions".	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 weeks.
Cmax,ss of BEVZ92 and Avastin®	Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss )	Cmax, ss: 0 to 336 hours post-dose after the administration of Cycle 7 infusion (Week 13)
Ctrough,sd of BEVZ92 and Avastin®	Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd )	Ctrough, sd: 0 to 336 hours after start of the first infusion.
Ctrough,ss of BEVZ92 and Avastin®	Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss)	Ctrough, ss: 0 to 336 hours after the administration of the Cycle 7 infusion.
Elimination Half-life (t1/2) of BEVZ92 and Avastin®	Secondary PK endpoints included the t1/2 calculated at Cycle 7	t1/2: 0 to 336 hours after the administration of the Cycle 7 infusion.
Elimination Rate Constant (Kel) of BEVZ92 and Avastin®	Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss)	Kel: 0 to 336 hours after the administration of the Cycle 7 infusion.
Volume of Distribution (Vd) of BEVZ92 and Avastin®	Secondary PK endpoints included the Vd calculated at Cycle 7	Vd: 0 to 336 hours after the administration of the Cycle 7 infusion.

Collaborators and Investigators

• Sponsor: mAbxience Research S.L.
• Collaborators: Laboratorio Elea Phoenix S.A.; Libbs Farmacêutica LTDA

Publications and helpful links

General Publications

• Romera A, Peredpaya S, Shparyk Y, Bondarenko I, Mendonca Bariani G, Abdalla KC, Roca E, Franke F, Melo Cruz F, Ramesh A, Ostwal V, Shah P, Rahuman SA, Paravisini A, Huerga C, Del Campo Garcia A, Millan S. Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018 Dec;3(12):845-855. doi: 10.1016/S2468-1253(18)30269-3. Epub 2018 Sep 24. Erratum In: Lancet Gastroenterol Hepatol. 2018 Sep 28;:

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: February 14, 2014
• First Submitted That Met QC Criteria: February 21, 2014
• First Posted (Estimate): February 24, 2014

Study Record Updates

• Last Update Posted (Actual): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 19, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: colorectal cancer; metastatic; first-line treatment; comparability
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid
• Other Study ID Numbers: BEVZ92-A-01-13 (Registry Identifier: BEVZ92-A-01-13)